Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing

Tourancheau, Alan; Margaillan, Guillaume; Rouleau, Michèle; Gilbert, Isabelle; Villeneuve, Lyne; Lévesque, Éric; Droit, Arnaud; Guillemette, Chantal

doi:10.1038/tpj.2015.20

Cited by 33 publications

(75 citation statements)

References 40 publications

(60 reference statements)

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“…In our previous study, we used the pyrosequencing technology that produces longer reads combined to cDNA libraries enriched for UGT sequences to reconstruct the most complete UGT transcriptome landscape in human tissues 8 . However, this approach did not allow the quantification of UGT variant expression levels.…”

Section: Resultsmentioning

confidence: 99%

“…The newly discovered UGT transcripts that were experimentally validated are named with the prefix 'v' (UGT_v#), while the remaining UGT transcripts are designated with the prefix 'n' (UGT_n#) 8 .…”

Section: Resultsmentioning

confidence: 99%

“…RNA samples and preparation of sequencing libraries was described recently. 8 Libraries were sequenced on an Illumina HiSeq 2500 system (McGill University and Génome Québec Innovation Center, Montreal, QC, Canada).…”

Section: Rna Samples Sequencing Librariesmentioning

confidence: 99%

“…8 Normalized expression was determined from mapped read files (.bam) with Cufflinks suite of tools (v2.2.1, parameters: --max-bundlefrags 10000000) and is given in Fragments Per Kilobase of transcript per Million mapped reads (FPKM). Cuffquant and Cuffdiff analysis were performed with the annotation used for the mapping step with default library normalization and crossreplicate dispersion estimation methods.…”

Section: Processing and Analysis Of Sequencing Datamentioning

confidence: 99%

“…7 At present, AS is best characterized for the ten genes encoding UGT1 and UGT2 enzymes, from which as many as 180 transcripts may be derived. 8 This collection of mRNAs was reconstructed following parallel sequencing, which provided long reads that encompass several exon-exon junctions. It allowed a precise assignment of reads to the appropriate UGT loci as well as transcript reconstruction but this approach did not permit quantification of UGT transcripts.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

et al. 2017

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Rna Samples Sequencing Librariesmentioning

confidence: 99%

Section: Processing and Analysis Of Sequencing Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

et al. 2017

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Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

et al. 2019

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An association between genetic variants in the vitamin D receptor ( VDR ) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets ( EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5 , CYP2R1 , CYP27B1 , CYP24A1 , CYP11A1 , and GC ). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10 −6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10 −5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10 −5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

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Quantitative analysis of the UDP‐glucuronosyltransferase transcriptome in human tissues

Zhou,

Montalvo,

Collins

et al. 2023

Pharmacology Res & Perspec

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UDP‐glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that play important roles in the detoxification of endogenous and exogenous substrates. The 22 human UGTs belong to four families (UGT1, UGT2, UGT3, and UGT8) and differ in their expression, substrate specificity, UDP‐sugar preference, and physiological functions. Differential expression/activity of the UGTs contributes to interperson variability in drug responses and toxicity, hormone homeostasis, and disease/cancer risks. However, in normal tissues, the tissue‐specific expression profiles and transcriptional regulation of the UGTs are still not fully understood. In this study, we comprehensively analyzed the transcriptome of 22 UGTs in 54 human tissues/regions using RNAseq data from GTEx. We then validated the findings in the liver and small intestine samples using real‐time PCR. Our results showed large interindividual variability across tissues in the expression of each UGT and the overall composition of UGT pools, consisting of different UGTs and their splice isoforms. Our results also revealed coexpression of the UGTs, Cytochrome P450s, and many transcription factors in the liver, suggesting potential coregulation or functional coordination. Our results provide the groundwork for future studies to detail further the regulation of the expression and activity of the UGTs.

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Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing

Cited by 33 publications

References 40 publications

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

Quantitative analysis of the UDP‐glucuronosyltransferase transcriptome in human tissues

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